Project Summary/Abstract The first step of a successful viral infection is virus attachment to a cell-surface receptor. The recent discovery that histo-blood group antigens (HBGAs) may be potential rotavirus (RV) receptors has significantly improved our understanding of RV epidemiology, disease burden, and pathogenesis. However, RVs exhibit significant diversity and are capable of causing disease in many different populations and animal species, making it difficult to develop broadly effective vaccines against RVs. As examples, the P[6] and P[11] RVs recognize HBGA precursors or intermediate products and revealed unique age-specific host ranges in neonates and young infants, further complicating strategies for safe and effective vaccine delivery. In addition, both P[6] and P[11] RVs are commonly found in developing countries, likely due to a human genetic predisposition for unique HBGA types (Lewis negative) and zoonotic transmission of these two genotypes in rural areas, and may require a cocktail vaccine including P[6] and/or P[11] RVs to confer broad protection to children. In this application, we will perform field surveillance of RV infection in South African children to better understand the high prevalence of P[6] RVs, among other circulating genotypes, and guide improvement of current RV vaccines and/or development of new vaccines against RVs. Two aims will be fulfilled: First, we will evaluate circulating RV strains and their HBGA binding patterns in children to verify the HBGA-specific host ranges of major circulating RV P types in African children. A two-year surveillance of RV gastroenteritis in neonates and young infants will be performed at two sentinel sites. Special attention will be paid to the roles of specific HBGAs, such as the type 1 chain precursors, during P[6] RV infection in children. We will also assess the antigenic relatedness among major circulating human RVs and compare them to the current RV vaccine strains to identify additional potential targets for future vaccines. Second, we will study the age-specific tropism of P[6] and P[11] RVs in neonates and young infants. The age-windows for infection with specific RV P types will be determined through the RV surveillance in Aim 1. A cohort with monthly saliva samples from neonates and young infants from birth to one year of age will be collected to define the age-windows of expression for specific HBGA receptors that bind P[6] and P[11] RVs. Knowledge gained through these studies is valuable to design a vaccination program for safe and effective delivery of these vaccine strains. Finally, to advance the next generation of RV vaccines, we will study the biological properties and usefulness of a live, attenuated P[6] RV, developed in our group, as a potential candidate in a new cocktail vaccine against RVs.